Circulation, Vol 83, 1333-1342, Copyright © 1991 by American Heart Association
Y Christen, B Waeber, J Nussberger, M Porchet, RM Borland, RJ Lee, K Maggon, L Shum, PB Timmermans and HR Brunner
BACKGROUND. The purpose of the present study was to assess the inhibitory
effect of DuP 753, an orally active angiotensin II receptor antagonist, on
the pressor action of exogenous angiotensin I and II in healthy male
volunteers. METHODS AND RESULTS. In the first study (single-dose study),
eight volunteers were included in a 2-day protocol repeated four times at
1-week intervals. In each phase, a different dose of drug (2.5, 5, 10, 20,
or 40 mg) or placebo was given. The peak systolic blood pressure response
to a test-dose of angiotensin I was determined serially before and after
oral administration of DuP 753 by continuously monitoring finger blood
pressure using a photoplethysmographic method. DuP 753 reduced the systolic
blood pressure response to angiotensin I in a dose-dependent fashion.
Three, 6, and 13 hours after the 40-mg dose, blood pressure response
decreased to 31 +/- 5%, 37 +/- 6%, and 45 +/- 3% of the control values
(mean +/- SEM, n = 7), respectively. In the second study, 29 volunteers
were treated for 8 days with either a placebo or DuP 753 (5, 10, 20, or 40
mg p.o. q.d.) and challenged on the first, fourth, and eighth days with
bolus injections of angiotensin II. Again, the inhibitory effect on the
systolic blood pressure response to angiotensin II was clearly dose
dependent. Six hours after 40 mg DuP 753, the systolic blood pressure
response to the test-dose of angiotensin II was reduced to 37 +/- 7%, 40
+/- 4%, and 38 +/- 6% of baseline values (mean +/- SEM, n = 6) on days 1,
4, and 8, respectively. With this latter dose, there was still a blocking
effect detectable 24 hours after the drug. Similar to angiotensin
converting enzyme and renin inhibitors, DuP 753 induced a dose-dependent
increase in plasma renin that was more pronounced on the eighth than on the
first day of drug administration. In these normal volunteers, no consistent
clinically significant side effects were observed. There was no evidence
for an agonist effect. CONCLUSIONS. DuP 753 appears to be a well-tolerated,
orally active, potent, and long- lasting antagonist of angiotensin II in
men.
ARTICLES
Oral administration of DuP 753, a specific angiotensin II receptor antagonist, to normal male volunteers. Inhibition of pressor response to exogenous angiotensin I and II
Hypertension Division, University Hospital, Lausanne, Switzerland.
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